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81.
Giovanni Monaco Elke Decrock Koen Nuyts Larry E. Wagner II Tomas Luyten Sergei V. Strelkov Ludwig Missiaen Wim M. De Borggraeve Luc Leybaert David I. Yule Humbert De Smedt Jan B. Parys Geert Bultynck 《PloS one》2013,8(8)
The anti-apoptotic Bcl-2 protein is the founding member and namesake of the Bcl-2-protein family. It has recently been demonstrated that Bcl-2, apart from its anti-apoptotic role at mitochondrial membranes, can also directly interact with the inositol 1,4,5-trisphosphate receptor (IP3R), the primary Ca2+-release channel in the endoplasmic reticulum (ER). Bcl-2 can thereby reduce pro-apoptotic IP3R-mediated Ca2+ release from the ER. Moreover, the Bcl-2 homology domain 4 (Bcl-2-BH4) has been identified as essential and sufficient for this IP3R-mediated anti-apoptotic activity. In the present study, we investigated whether the reported inhibitory effect of a Bcl-2-BH4 peptide on the IP 3R1 was related to the distinctive α-helical conformation of the BH4 domain peptide. We therefore designed a peptide with two glycine “hinges” replacing residues I14 and V15, of the wild-type Bcl-2-BH4 domain (Bcl-2-BH4-IV/GG). By comparing the structural and functional properties of the Bcl-2-BH4-IV/GG peptide with its native counterpart, we found that the variant contained reduced α-helicity, neither bound nor inhibited the IP 3R1 channel, and in turn lost its anti-apoptotic effect. Similar results were obtained with other substitutions in Bcl-2-BH4 that destabilized the α-helix with concomitant loss of IP3R inhibition. These results provide new insights for the further development of Bcl-2-BH4-derived peptides as specific inhibitors of the IP3R with significant pharmacological implications. 相似文献
82.
Annique C. Dombrowsky Karin Burger Ann-Kristin Porth Marlon Stein Martin Dierolf Benedikt Gnther Klaus Achterhold Bernhard Gleich Annette Feuchtinger Stefan Bartzsch Elke Beyreuther Stephanie E. Combs Franz Pfeiffer Jan J. Wilkens Thomas E. Schmid 《Radiation and environmental biophysics》2020,59(1):111-120
Microbeam radiation therapy (MRT), a preclinical form of spatially fractionated radiotherapy, uses an array of microbeams of hard synchrotron X-ray radiation. Recently, compact synchrotron X-ray sources got more attention as they provide essential prerequisites for the translation of MRT into clinics while overcoming the limited access to synchrotron facilities. At the Munich compact light source (MuCLS), one of these novel compact X-ray facilities, a proof of principle experiment was conducted applying MRT to a xenograft tumor mouse model. First, subcutaneous tumors derived from the established squamous carcinoma cell line FaDu were irradiated at a conventional X-ray tube using broadbeam geometry to determine a suitable dose range for the tumor growth delay. For irradiations at the MuCLS, FaDu tumors were irradiated with broadbeam and microbeam irradiation at integral doses of either 3 Gy or 5 Gy and tumor growth delay was measured. Microbeams had a width of 50 µm and a center-to-center distance of 350 µm with peak doses of either 21 Gy or 35 Gy. A dose rate of up to 5 Gy/min was delivered to the tumor. Both doses and modalities delayed the tumor growth compared to a sham-irradiated tumor. The irradiated area and microbeam pattern were verified by staining of the DNA double-strand break marker γH2AX. This study demonstrates for the first time that MRT can be successfully performed in vivo at compact inverse Compton sources. 相似文献
83.
Elke Uribe Thomas J. Steele Robert C. Richards K. Vanya Ewart 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
An Atlantic salmon (Salmo salar) C-type lectin (SSL) binds to mannose and related sugars as well as to the surface of Aeromonas salmonicida. To characterize this lectin as a pathogen recognition receptor in salmon, aspects of its interaction with molecules and with intact pathogens were investigated.Methods
SSL was isolated using whole-yeast-affinity and mannan-affinity chromatography. The binding of SSL to the two major surface molecules of A. salmonicida, lipopolysaccharide (LPS) and A-layer protein was investigated by western blotting and enzyme-linked immunosorbent assays. Microbial binding specificity of SSL was examined by whole cell binding assays using a range of species. Carbohydrate ligand specificity of SSL was examined using glycan array analysis and frontal affinity chromatography.Results
SSL showed binding to bacteria and yeast including, Pseudomonas fluorescens, A. salmonicida, A. hydrophila, Pichia pastoris, and Saccharomyces cerevisiae, but there was no detectable binding to Yersinia ruckeri. In antimicrobial assays, SSL showed no activity against Escherichia coli, Bacillus subtilis, S. cerevisiae, or A. salmonicida, but it was found to agglutinate E. coli. The major surface molecule of A. salmonicida recognized by SSL was shown to be LPS and not the A-layer protein. LPS binding was mannose-inhibitable. Glycans containing N-acetylglucosamine were shown to be predominant ligands.Conclusion
SSL has a distinct ligand preference while allowing recognition of a wide variety of related carbohydrate structures.General Significance
SSL is likely to function as a wide-spectrum pattern recognition protein. 相似文献84.
CRISPRmap: an automated classification of repeat conservation in prokaryotic adaptive immune systems
Sita J. Lange Omer S. Alkhnbashi Dominic Rose Sebastian Will Rolf Backofen 《Nucleic acids research》2013,41(17):8034-8044
Central to Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)-Cas systems are repeated RNA sequences that serve as Cas-protein–binding templates. Classification is based on the architectural composition of associated Cas proteins, considering repeat evolution is essential to complete the picture. We compiled the largest data set of CRISPRs to date, performed comprehensive, independent clustering analyses and identified a novel set of 40 conserved sequence families and 33 potential structure motifs for Cas-endoribonucleases with some distinct conservation patterns. Evolutionary relationships are presented as a hierarchical map of sequence and structure similarities for both a quick and detailed insight into the diversity of CRISPR-Cas systems. In a comparison with Cas-subtypes, I-C, I-E, I-F and type II were strongly coupled and the remaining type I and type III subtypes were loosely coupled to repeat and Cas1 evolution, respectively. Subtypes with a strong link to CRISPR evolution were almost exclusive to bacteria; nevertheless, we identified rare examples of potential horizontal transfer of I-C and I-E systems into archaeal organisms. Our easy-to-use web server provides an automated assignment of newly sequenced CRISPRs to our classification system and enables more informed choices on future hypotheses in CRISPR-Cas research: http://rna.informatik.uni-freiburg.de/CRISPRmap. 相似文献
85.
Atanas G. Atanasov Jian N. Wang Shi P. Gu Jing Bu Matthias P. Kramer Lisa Baumgartner Nanang Fakhrudin Angela Ladurner Clemens Malainer Anna Vuorinen Stefan M. Noha Stefan Schwaiger Judith M. Rollinger Daniela Schuster Hermann Stuppner Verena M. Dirsch Elke H. Heiss 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are clinically used to counteract hyperglycemia. However, so far experienced unwanted side effects, such as weight gain, promote the search for new PPARγ activators.Methods
We used a combination of in silico, in vitro, cell-based and in vivo models to identify and validate natural products as promising leads for partial novel PPARγ agonists.Results
The natural product honokiol from the traditional Chinese herbal drug Magnolia bark was in silico predicted to bind into the PPARγ ligand binding pocket as dimer. Honokiol indeed directly bound to purified PPARγ ligand-binding domain (LBD) and acted as partial agonist in a PPARγ-mediated luciferase reporter assay. Honokiol was then directly compared to the clinically used full agonist pioglitazone with regard to stimulation of glucose uptake in adipocytes as well as adipogenic differentiation in 3T3-L1 pre-adipocytes and mouse embryonic fibroblasts. While honokiol stimulated basal glucose uptake to a similar extent as pioglitazone, it did not induce adipogenesis in contrast to pioglitazone. In diabetic KKAy mice oral application of honokiol prevented hyperglycemia and suppressed weight gain.Conclusion
We identified honokiol as a partial non-adipogenic PPARγ agonist in vitro which prevented hyperglycemia and weight gain in vivo.General significance
This observed activity profile suggests honokiol as promising new pharmaceutical lead or dietary supplement to combat metabolic disease, and provides a molecular explanation for the use of Magnolia in traditional medicine. 相似文献86.
The adaptation of protein synthesis to environmental and physiological challenges is essential for cell viability. Here, we show that translation is tightly linked to the protein‐folding environment of the cell through the functional properties of the ribosome bound chaperone NAC (nascent polypeptide‐associated complex). Under non‐stress conditions, NAC associates with ribosomes to promote translation and protein folding. When proteostasis is imbalanced, NAC relocalizes from a ribosome‐associated state to protein aggregates in its role as a chaperone. This results in a functional depletion of NAC from the ribosome that diminishes translational capacity and the flux of nascent proteins. Depletion of NAC from polysomes and re‐localisation to protein aggregates is observed during ageing, in response to heat shock and upon expression of the highly aggregation‐prone polyglutamine‐expansion proteins and Aβ‐peptide. These results demonstrate that NAC has a central role as a proteostasis sensor to provide the cell with a regulatory feedback mechanism in which translational activity is also controlled by the folding state of the cellular proteome and the cellular response to stress. 相似文献
87.
88.
Bassam Al Atalah Elke Fouquaert Els J. M. Van Damme 《Plant Molecular Biology Reporter》2013,31(6):1315-1324
In this study, the promoter activity for three types of Euonymus-related lectins (EUL) from rice, further referred to as OrysaEULS2, OrysaEULS3, and OrysaEULD1A was analyzed. In silico promoter analyses showed that the EUL promoters from rice contain next to the typical promoter elements some motifs that are considered to be stress-responsive elements. Furthermore, Arabidopsis thaliana plants were transformed with a promoter::β-glucuronidase (GUS) construct for each of the proteins under study. Subsequently, one-insertion homozygous lines were selected and analyzed for GUS activity. Experiments were performed under normal growth conditions or after application of different stress conditions, in particular treatments with 150 mM NaCl, 100 mM mannitol, and 100 μM abscisic acid (ABA) for 24 h. GUS activity was detected with the OrysaEULS3 and OrysaEULD1A promoters especially in the cotyledons and the young true leaves, respectively, but not with the OrysaEULS2 promoter. The activity of OrysaEULS3 and OrysaEULD1A promoters was increased after ABA and mannitol treatments but decreased after NaCl treatment. We hypothesize that the Euonymus-related rice proteins have a role in sensing and responding to external stresses as well as in the growth of the plant. 相似文献
89.
ABSTRACTThe synchrony effect (i.e. superior performance at optimal, inferior performance at suboptimal times of day) has been broadly studied within the context of circadian rhythms. Whether one chronotype copes better with the synchrony effect than the other received only insufficient empirical attention. We report on an applied experimental study investigating the impact of chronotype on the synchrony effect in a semantic analogy task. To detect an analogy, 36 participants (12 males) aged between 18 and 40 had to decide whether the relation between events of a source pair was mirrored by the relation between events of a target pair (e.g. to cook: to eat = to saddle: to ride). Temporal orientation of the relation within each event pair was varied corresponding either to the chronological or reverse order. Response times (RTs), error rates, as well as the psychophysiological parameters pre-experimental pupil baseline and peak pupil dilation replicate findings of a synchrony effect (shorter RTs and allocation of less cognitive resources at optimal times of day) and show an impact of chronotype (morning types generally outperforming evening types). Most importantly, morning types appeared to cope better with the synchrony effect than evening types: At suboptimal times, morning types solved the analogy detection task more efficient; that is faster with the same accuracy and without the investment of more cognitive resources. They also showed greater alertness and wakefulness indexed by greater pre-experimental pupil baselines. At optimal times of day, morning types have more cognitive resources available to allocate these to the more demanding conditions to outperform evening types. We interpret these findings to suggest that morning types are more able to adapt to unfavourable circumstances (for instance, by avoiding wasteful resource allocation when there are less cognitive resources available). Evening types appear less able to adapt to suboptimal times than morning types, because they have to deal with social jetlag and decreased self-control. 相似文献
90.
Yu Tong Elke Gabriel-Neumann Benard Ngwene Angelika Krumbein Susanne Baldermann Monika Schreiner Eckhard George 《Plant and Soil》2013,372(1-2):361-374